Diabetes is a dysbolism characterized by the chronic hyperglycemia which is caused by shortage of insulin and so on, and it is classified into Type 1 diabetes and Type 2 diabetes according to the cause of appearance of the symptoms. Type 1 diabetes is caused and initiated by the destruction of the insulin secretion cell of the pancreas by virus or the autoimmunity, and is often found in the youth. An environmental factor including lifestyle, such as overeating, obesity and lack of exercise as well as the aging become a cause of Type 2 diabetes, and the symptoms of Type 2 diabetes appear after the middle age. The number of patients suffering from diabetes is estimated about 7,400 thousand in Japan, and 90 to 95% of them are classified into Type 2 diabetes. If these diabetics are left without sufficient treatment and a hyperglycemia state continues for a long time, their QOL will not only be spoiled remarkably, but the symptoms of the critical complications in connection with a prognosis of life will also appear. Typical complications are diabetic retinopathy, diabetic nephropathy, and diabetes neuropathic disorder with which the present invention is concerned.
Diabetes neuropathic disorder is also called diabetic neuropathy, and about two thirds of diabetics are said to suffer from some kinds of complications. Generally an obstacle appears from the part (nerve of a hand or a tip of a foot) governed by long nerve fibers, and then is followed by numbness and a pain at hand and foot, and an unusual feeling cold in the beginning, and if they are left without any treatment, the condition progresses and spreads toward the bodily center such as from the tip of a foot to the knee and from the hand to the elbow. The diversity of such a symptom is caused by the factors that various kinds of nerves such as a motor nerve, a sensory nerve and an autonomous nerve are impaired, and that various functions are managed by each of the different nerves respectively, and these are the factors that make the diagnosis and treatment of the diabetic neuropathy difficult.
The mechanism of the development of diabetic neuropathy has not yet been established, but a promotion of the activity in polyol pathway as well as a dysbolism of myo-inositol that relates thereto, an abnormality of the activity of protein kinase C (PKC) and an oxidative stress are assumed to be metabolic factors. Another theory is also proposed that the insufficiency of the supplement of oxygen and nutrition to the nerve tissue by a microcirculation disturbance in the endoneurium is a vascular factor. It is supposed that these are not abnormal respectively, but a mutual interaction between the metabolic factors and the vascular factors causes the development and progress of the symptoms of diabetic neuropathy under the condition that a hyperglycemia state continues over a long period of time.
Regarding the prophylaxis and treatment of the diabetic neuropathy, a management of the risk factor, namely that of the diabetes condition, is the basic point, as is common to that of diabetic complications. On the other hand, the development of therapeutic agents in line with the development mechanism is also being carried on aggressively, and the usefulness of an inhibitor of the aldose reductase as a rate-controlling enzyme that promote the activation of the polyol metabolism, which is one of the metabolic factors, is expected. Moreover, it has been found that the activity of PKC (β-isoform) increases under the diabetic state or the hyperglycemia condition, and it is said that a selective PKC-β inhibitor suppresses hypoperfusion in the vasa nervorum which is one of the factors of the diabetic neuropathy. Furthermore, it has been reported that the cell damage by increase of oxidative stress and the hypoperfusion by inhibition of NO production cause the fall of nerve functions in recent years, and the effectiveness of the agents having various kind of anti-oxidative activities and the transcription factors located in the down stream of oxidative stress is reported from the basic point of view.
However, these agents on the basis of the cause of development of the disease are poor in efficacy against a developed neuropathy, and the necessity of an agent for the symptomatic treatment to improve the QOL of a patient is actually high. Especially, non-steroidal anti-inflammatory agent cannot be applied to the so-called diabetic neuropathy, such as pain, numbness and nociceptive hypersensitivity. Tricyclic antidepressants, anti-convulsants and mexiletine are said to be effective at present, but a decisive treatment has not been established yet. Therefore, the situation to make it possible to select an appropriate agent for symptomatic treatment according to the condition of the patient is expected.
An object of the present invention is to provide an agent which is almost free from harmful side effect and is very efficacious for the treatment of diabetic neuropathy, especially an agent for the treatment of a subjective symptom such as pain accompanied with a diabetic neuropathy.